The present invention is generally directed to the preparation of N-carboxyanhydrides and, more specifically, to reducing or minimizing the chloride content of reaction mixtures in which N-carboxyanhydrides of amino acids are prepared.
N-carboxyanhydrides of amino acids are routinely used in the synthesis of polypeptides. For example, in U.S. Pat. No. 6,656,458, Philippe et al. describe the synthesis of polyamino acids from representative N-carboxyanhydrides such as sarcosine N-carboxyanhydride, threonine N-carboxyanhydride, serine N-carboxyanhydride, valine N-carboxyanhydride, norvaline N-carboxyanhydride, isoleucine N-carboxyanhydride, leucine N-carboxyanhydride, norleucine N-carboxyanhydride, lysine N-carboxyanhydride, phenylalanine N-carboxyanhydride, and tyrosine N-carboxyanhydride.
Several processes are known for preparing N-carboxyanhydrides. One method for producing N-carboxyanhydrides is the reaction of an amino acid or its salt with phosgene in a solvent medium. For example, in U.S. Pat. No. 4,267,344, Halstrom et al. disclose preparing N-carboxyanhydrides, in part, by bubbling phosgene through a solution of substituted amino acids and a solvent. In U.S. Pat. No. 6,603,016, Cornille et al. disclose preparing N-carboxyanhydrides by reacting amino acids with phosgene, diphosgene, or triphosgene in a solvent medium. In U.S. Pat. No. 6,479,665, Cornille et al. disclose preparing N-carboxyanhydrides by reacting amino acids with phosgene, diphosgene or triphosgene in a solvent medium wherein the reaction at least partially occurs in the presence of an unsaturated organic compound which has one or more ethylenic double bonds, the remainder of the molecule being inert to other compounds in the reaction mixture, and one of the carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms.
A general reaction scheme for the formation of an N-carboxyanhydride by reaction of an amino acid with phosgene is as follows:

During the formation of an N-carboxyanhydride by reaction of an amino acid or its salt with phosgene, a considerable amount of HCl is also produced. HCl in the reaction medium, in turn, can lead to the formation of chlorinated by-products which remain in the N-carboxyanhydride product, affecting purity and yield. For example, HCl can cause ring opening of tetrahydrofuran (a solvent commonly used in the reaction mixture) leading to the formation of 4-chlorobutyl chloroformate. Chlorinated compounds also affect polymerization reactions of N-carboxyanhydrides, because effective polymerization requires the absence, or a sufficiently low amount, of chlorinated compounds present in the N-carboxyanhydride monomers.
Various approaches have been used to reduce the concentration of HCl and chlorinated derivatives in the reaction product. In U.S. Pat. No. 5,135,754, Brack sweeps the reaction mixture with argon for at least 48 hours at 48° C.; see U.S. Pat. No. 5,135,754 at column 3, lines 50-52. Mallow heats the reaction product (a partial ester) to 40°-60° C. and purges with nitrogen to remove hydrogen chloride; see U.S. Pat. No. 5,945,558 at column 4, lines 38-41. Goodman et al. purge the reaction system with nitrogen for one hour before the reaction is initiated and, following the addition of phosgene, purge the reaction mixture with nitrogen for another two hours; see U.S. Reissue Pat. No. 30,170 at column 5, lines 6-12. In U.S. Pat. No. 6,603,016, Cornille et al. carry out the reaction, at least in part, at a pressure less than 1000 mbar. In general, however, these approaches tend to yield a product having a relatively high chloride content, are not well-suited for relatively large scale production, require a relatively long period of time for the phosgene, diphosgene or triphosgene to react with the amino acid, and/or require a quiescent reaction mixture. Additionally, the intermediate N-carboxyanhydride created during the reaction of phosgene, diphosgene or triphosgene with the amino acid is relatively unstable, and may decompose during the longer reaction time required for large scale production.